Glycogen storage diseases and glycogen metabolism disorders are a series of diseases that are caused by defects in basic metabolizing enzymes, thereby resulting in defects in glycogen synthesis or breakdown within muscles, liver, neurons and other cell types. Glycogen storage diseases may be either genetic (usually as autosomal recessive disorders) or acquired (e.g., by intoxication with alkaloids) (Monga et al., 2011, Molecular Pathology of Liver Diseases, Molecular Pathology Library 5, Chapter 45). There are a number of different types of glycogen storage diseases, including GSDs Types I-XI, GSD Type 0, as well as Lafora disease which is often termed a glycogen metabolism disorder. These diseases differ with regard to the enzyme that is mutated and/or primary tissue affected (Monga et al. and Gentry, et al., 2013, FEBS J, 280(2):525-37).
a. Forbes-Cori Disease
Forbes-Cori Disease, also known as GSD Type III, GSD III, or glycogen debrancher deficiency, is an autosomal recessive neuromuscular/hepatic disease with an estimated incidence of 1 in 100,000 births. These terms are used interchangeably throughout. Forbes-Cori Disease represents approximately 27% of all Glycogen Storage Disorders. The clinical picture in Forbes-Cori Disease is reasonably well established but exceptionally variable. Although generally considered a disease of the liver, with hepatomegaly and cirrhosis, Forbes-Cori Disease also is characterized by abnormalities in a variety of other systems. Muscle weakness, muscle wasting, hypoglycemia, dyslipidemia, and occasionally mental retardation also may be observed in this disease. Some patients possess facial abnormalities. Some patients also may be at an increased risk of osteoporosis. Different patients may suffer from one, or more than one, of these symptoms. The differences in clinical manifestations of this disease are often associated with different subtypes of this disease.
There are four subtypes of Forbes-Cori Disease. The Type A subtype accounts for approximately 80% of the cases, lacks enzymatic activity (e.g., both glucosidase and transferase activities associated with native enzymatic activity) and affects both the liver and muscle. The Type B subtype accounts for approximately 15% of the cases, lacks enzymatic activity (e.g., both glucosidase and transferase activities associated with native enzymatic activity) and affects only the liver. The Type C and D subtypes account for less than 5% of the cases, are associated with selective loss of glucosidase activity (Type C) or transferase activity (Type D) and are clinically similar to the Type A subtype.
Forbes-Cori Disease is caused by mutations in the AGL gene. The AGL gene encodes the amylo-1,6-glucosidase (AGL) protein (GenBank Accession Nos. NP_000019.2; NM_000645.2; and NM_000646.2) which is a cytoplasmic enzyme responsible for catalyzing the cleavage of terminal α-1,6-glucoside linkages in glycogen and similar molecules. The AGL protein has two separate enzymatic activities: 4-alpha-glucotransferase activity and amylo-1,6-glucosidase activity. Both catalytic activities are required for normal glycogen debranching activity. Glycogen is a highly branched polymer of glucose residues.
AGL is responsible for transferring three glucose subunits of glycogen from one parallel chain to another, thereby shortening one linear branch while lengthening another. Afterwards, the donator branch will still contain a single glucose residue with an alpha-1,6 linkage. The alpha-1,6 glucosidase of AGL will then remove that remaining residue, generating a “de-branched” form of that chain on the glycogen molecule. Without proper glycogen de-branching, as occurs in the absence of functional AGL, abnormal glycogens resembling an amylopectin-like structure (polyglucosan) result and accumulate in various tissues in the body, including hepatocytes and myocytes. This abnormal form of glycogen is typically insoluble and may be toxic to cells.
Currently, the primary treatment for Forbes-Cori is dietary and is aimed at maintaining normoglycemia (Ozen, et al., 2007, World J Gastroenterol, 13(18): 2545-46). To achieve this, patients are fed frequent meals high in carbohydrates and cornstarch supplements. Patients having myopathy are also fed a high-protein diet. Liver transplantation resolves all liver-related biochemical abnormalities, but the long-term effect of liver transplantation on myopathy/cardiomyopathy is unknown (Ozen et al., 2007). These tools for managing Forbes-Cori are inadequate. Dietary regimens have significant compliance problems—particularly with young patients. As such, there is a need for a Forbes-Cori therapy that reduces the build-up of glycogen and/or polyglucosan.
b. Andersen's Disease
Glycogen storage disease type IV (GSD IV), also known as Andersen Disease, Andersen's Disease or amylopectinosis (and these terms are used interchangeably herein), is a rare autosomal recessive disorder caused by deficiency of the glycogen branching enzyme (GBE) (GenBank Accession No. NP_000149.3), also called amylo-(1,4 to 1,6) transglycosylase. GBE produces α-1,6 branches in glucose through a process involving the terminal transfer of a terminal fragment of 6-7 glucose residues (from a polymer of at least 11 glucose residues in length) to an internal glucose residue at the C-6 hydroxyl position. In humans, the GBE1 gene is present on chromosome 3p12 and encodes a peptide having 702 amino acids.
Reduced or absent levels of GBE result in tissue accumulation of abnormal glycogen with fewer branch points and longer outer branches that resembles an amylopectin-like structure, also known as polyglucosan (Lee, et al., 2010, Hum Mol Genet, 20(3):455-465). Polyglucosan has low solubility and may form precipitates in the liver, heart and muscle.
Andersen disease is clinically heterogeneous, with variable tissue involvement and age of onset (Akman, 2014, Neurology, 82(1):P1.054). The age of onset ranges from fetus to adulthood and is divided into four groups: (i) perinatal, presenting as fetal akinesia deformation sequence and perinatal death; (ii) congenital (infantile), with hydrops fetalis, neuronal involvement and death in early infancy; (iii) childhood (juvenile), with myopathy or cardiomyopathy; and (iv) adult, with isolated myopathy or adult polyglucosan body disease (Lee, et al., 2010). Absence of enzyme activity is usually lethal in utero or in infancy, affecting primarily muscle and liver. However, residual enzyme activity (5-20%) leads to a juvenile or adult-onset disorder that affects primarily muscle and both central and peripheral nervous systems. Patients having juvenile Andersen Disease, which is the most common form of Andersen Disease, first display symptoms within the first few months of life and are characterized by hepatosplenomegaly and failure to thrive. The juvenile cases then typically progress to liver cirrhosis, portal vein hypertension, esophageal varices and ascites, with death usually occurring by five years of age. Adult cases of Andersen Disease may manifest similar symptoms as juvenile cases, but the onset of these symptoms does not occur until later in the patient's lifetime.
Treatment of Andersen Disease is usually dietary, by maintaining blood glucose along with adequate nutrient intake in order to improve liver function and muscle strength. In cases of progressive liver failure, liver transplants may be employed. Similar to the therapies for Forbes-Cori Disease, these tools for managing Andersen Disease are inadequate and the disease is or can be fatal. As such, there is a need for an Andersen Disease therapy that reduces glycogen and/or polyglucosan accumulation.
c. von Gierke's Disease
Glycogen storage disease type I (GSD I) or von Gierke's disease (also referred to in the art and herein interchangeably as von Gierke Disease), is the most common of the glycogen storage diseases with an incidence of approximately 1 in 50,000 to 100,000-births. The deficiency impairs the ability of the liver to produce free glucose from glycogen and from gluconeogenesis. Since these are the two principal metabolic mechanisms by which the liver supplies glucose to the rest of the body during periods of fasting, it causes severe hypoglycemia and results in increased glycogen storage in liver and kidneys. This can lead to enlargement of both organs.
The most common forms of GSD I are designated GSD Ia and GSD Ib, the former accounting for over 80% of diagnosed cases and the latter for less than 20%. A few rarer forms have been described. GSD Ia results from mutations of G6PC, the gene for glucose-6-phosphatase. GSD Ib results from mutations of the SLC37A4, the glucose-6-phosphatase transporter.
Clinical manifestations result, directly or indirectly, from: the inability to maintain an adequate blood glucose level during the post-absorptive hours of each day; organ changes due to glycogen accumulation; excessive lactic acid generation; and damage to tissue from hyperuricemia. Glycogen accumulation includes accumulation in the liver and in the kidneys and small intestines. Hepatomegaly, usually without splenomegaly, begins to develop in fetal life and is usually noticeable in the first few months of life. By the time the child is standing and walking, the hepatomegaly may be severe enough to cause the abdomen to protrude.
The kidneys are usually 10 to 20% enlarged with stored glycogen. This does not usually cause clinical problems in childhood, with the occasional exception of a Fanconi syndrome with multiple derangements of renal tubular reabsorption, including proximal renal tubular acidosis with bicarbonate and phosphate wasting. However, prolonged hyperuricemia can cause uric acid nephropathy. In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to renal failure.
Hepatic complications have been serious in some patients. Adenomas of the liver can develop in the second decade or later, with a small chance of later malignant transformation to hepatoma or hepatic carcinomas. Additional problems reported in adolescents and adults with GSD I have included hyperuricemic gout, pancreatitis, and chronic renal failure.
Treatment of von Gierke's disease is usually dietary, by frequent feedings of foods high in glucose or starch (which is readily digested to glucose), with the primary treatment goal being prevention of hypoglycemia and the secondary metabolic derangements. Particularly in children, this requires feedings throughout the night. Two methods have been used to achieve this goal in young children: (1) continuous nocturnal gastric infusion of glucose or starch; and (2) night-time feedings of uncooked cornstarch. However, there remains a need for von Gierke's disease therapies, for example, therapy that reduces glycogen accumulation in the liver and/or kidney of patients with GSD I, such as GSD Ia or GSD Ib.
d. Lafora Disease
Lafora Disease, also called Lafora progressive myoclonic epilepsy or MELF, is a rare, fatal neurodegenerative disorder characterized by the accumulation of insoluble, poorly branched, hyperphosphorylated glycogen in cells from most tissues of affected individuals, including the brain, heart, liver, muscle and skin. Lafora Disease patients typically first develop symptoms in adolescence. Symptoms include temporary blindness, depression, seizures, drop attacks, myoclonus, ataxia, visual hallucinations, absences, and quickly developing and severe dementia. Death usually occurs 2-10 years (5 years mean) after onset.
The prevalence of Lafora Disease is unknown. While this disease occurs worldwide, it is most common in Mediterranean countries, parts of Central Asia, India, Pakistan, North Africa and the Middle East. In Western countries, the prevalence is estimated to be below 1/1,000,000.
Lafora Disease is an autosomal recessive disorder caused by mutations in one of two genes: EPM2A and EPM2B. EPM2A encodes for the 331 amino acid protein known as laforin, which comprises an amino-terminal carbohydrate binding module and a carboxy-terminal dual specificity phosphatase domain. EPM2B encodes for the E3 ubiquitin ligase known as malin. Together, laforin and malin make up a functional complex which is believed to be involved in negatively regulating glucose uptake by modulating the subcellular localization of glucose transporters. Singh et al., 2012, Mol Cell Biol, 32(3):652-663. Recent studies also suggest that the accumulation of glycogen is responsible for neurodegeneration and impaired autophagy observed in the brains of Lafora patients. Duran et al., 2014, Hum Mol Genet, 23(12): 3147-56.
There is currently no cure or effective treatment for patients having Lafora Disease. However, the seizures and myoclonus can be managed, at least in early stages of the disease, with antiepileptic medications.